Link between Brain, Bone in Alzheimer's Disease Identified

Researchers at NEOMED have just identified a major connection between areas of the brainstem—the ancient area that controls mood, sleep, and metabolism—and detrimental changes to bone in a preclinical model of Alzheimer's disease (AD). The study, titled "Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer's Disease," is led by Christine Dengler-Crish, PhD, assistant professor of pharmaceutical sciences, and anatomy and neurobiology, and will be published in the upcoming issue of the Journal of Alzheimer's Disease, an international multidisciplinary journal that reports progress in understanding the causes, symptoms, and treatment of Alzheimer's.

More than five million Americans are living with Alzheimer's disease. Along with being the sixth leading cause of death in the U.S., Alzheimer's has major social, emotional, and financial consequences for patients and their families. Incurable and seemingly unstoppable, less than 5 percent of AD cases are due to a clear genetic reason, so it is hard to predict who will be at risk for acquiring this devastating disease.

Dr. Dengler-Crish and her research team that included graduate students Matthew Smith (NEOMED) and Gina Wilson (Kent State University) report that early reductions in bone mineral density (BMD) that occur in a preclinical model of AD are due to degeneration in an area of the brainstem that produces the majority of the brain's serotonin—a neurochemical that controls mood and sleep, which are two processes that are also affected early in AD.

One's bones may be one of the earliest indicators of brain degeneration in Alzheimer's disease

Reduced BMD, which sometimes leads to osteoporosis, translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. Furthermore, Dr. Dengler-Crish's research suggests that early bone loss and serotonin deficiency in AD may tell us something very important about how we approach diagnosing and treating this disease.

"Measurement of bone density, which is routinely performed in the clinic, could serve as a useful biomarker for assessing AD risk in our aging population," notes Dr. Dengler-Crish. "The findings of this study motivate us to explore the serotonin system as a potential new therapeutic target for this devastating disease."

Dengler-Crish, who received her bachelor's degree from Baldwin Wallace University, her master's in psychology from the University of Illinois at Chicago and her PhD in neuroscience from Vanderbilt University, has now been named an associate editor for the Journal of Alzheimer's Disease. She is excited to facilitate the work of other scientists in this important area. "I am thrilled to be able to assist the publication of researchers' innovative work, here and across the world, that is desperately needed to combat these currently incurable chronic diseases. Now more than ever, there is hope that we soon will be able to slow, stop or reverse the progression of these destructive neurodegenerative conditions."

"This is extremely exciting and has significant translational potential and relevance to early detection of the disease," noted Jason R Richardson, PhD, DABT, director for Neurodegenerative Disease and Aging Research at NEOMED.

CBD Oil May Reduce Frequency and Severity of Epileptic Seizures

Cannabidiol oil, also known as CBD oil, reduces the frequency and severity of seizures in children and adults with severe, intractable epilepsy, according to findings presented by researchers from the University of Alabama at Birmingham at the American Epilepsy Society 70th Annual Meeting.

UAB researchers presented eleven abstracts, or research findings, at the meeting. A key finding was that CBD provided a significant reduction in frequency of seizures for a majority of the patients in the study, and that approximately two-thirds of patients saw a greater than 50 percent reduction in severity.

“It is encouraging that both frequency and severity of seizures appear to improve in the majority of patients in our study, patients who have limited treatment options,” said Jerzy P. Szaflarski, MD, PhD, professor in the Department of Neurology and director of the UAB Epilepsy Center. “Our research adds to the evidence that CBD may reduce frequency of seizures, but we also found that it appears to decrease the severity of seizures, which is a new finding.”

The results were based on an open-label study of 81 patients—42 children and 39 adults—who experienced four or more seizures per month. UAB launched the studies of CBD oil as a treatment for severe, intractable seizures in April 2015. The studies, an adult study at UAB and a pediatric study at Children’s of Alabama, were authorized by the Alabama Legislature in 2014 by legislation known as Carly’s Law.

After one month of beginning CBD therapy, 68 percent of the patients had experienced a greater than 25 percent reduction in seizure frequency, 58 percent had a greater than 50 percent reduction, 36 percent had a greater than 75 percent reduction, and 9 percent were seizure-free. Those results were maintained at three and six months.

To assess seizure severity, researchers led by Jenifer DeWolfe, MD, associate professor of neurology, used the Chalfont Seizure Severity Scale, a questionnaire given prior to therapy and re-administered at intervals throughout treatment. Fifty-seven patients were followed for three months: 67 percent experienced a more than 50 percent decrease in seizure severity, while 33 percent did not. Of 47 patients followed for six months, 64 percent had a greater than 50 percent decrease in seizure severity and 36 percent did not.

“These are encouraging results, but it is important to note that each patient may respond differently to CBD, and the dose for optimal seizures control varies,” said Martina Bebin, MD, professor of neurology and co-primary investigator of the CBD studies. “There appears to be an optimal CBD dose range where the patient achieves maximum benefit. If outside this CBD dosing range, the seizure frequency may not improve and may even increase. More research is needed, including determining why and how CBD helps some people with epilepsy but not others.”

Among the other UAB abstracts presented at the AES meetings:

·CBD oil was associated with an improvement in mood, an effect independent of the extent of seizure reduction. Lead author Pongkiat Kankirawatana, MD, professor of pediatrics, says CBD oil may have overall positive effects on mood, which should be further investigated in patients with epilepsy and other chronic conditions in controlled studies.

·A study led by Szaflarski and Bebin found that the optimum dose in both children and adults was between 20 and 25 mg/kg/day.

·Jane Allendorfer, MD, assistant professor of neurology, found that CBD, in a selected group of patients with epilepsy who experienced overall improved seizure control, has the potential for positive cognitive effects that are associated with corresponding fMRI signal changes.

·One abstract reports on an interaction between warfarin, a drug used as an anticoagulant, and CBD. This underscores the importance of monitoring appropriate laboratory work in patients receiving CBD oil along with other medications, according to study lead Brannon Vines, MD, a clinical neurophysiology fellow.

·Significant drug interactions were identified between CBD and commonly-used medications for epilepsy, including clobazam, rufinamide, topiramiate, zonisamide, and eslicarbazepine. This study, led by neurology fellow Tyler Gaston, MD, emphasizes the importance of monitoring anti-epilepsy drug levels during treatment with CBD.

·Electrical discharges measured by EEG decreased significantly after initiation and maintenance of CBD, particularly in pediatric patients, according to a study led by Leslie Grayson, MD, a neurology fellow.

·Using fMRI imaging, Amber Gregory, a graduate student in psychology, showed that persons with epilepsy showed gains in working memory that were associated with a shift in neural recruitment as examined with functional MRI.

·An abstract aimed at examining associations between social determinants of health, such as age, gender and socioeconomic factors against health status, quality of life and mood states showed that higher age and low income were associated with lower health ratings among epilepsy patients, according to study led Magdalena Szaflarski, PhD, assistant professor of sociology.

The studies are designed to test the safety and tolerability of CBD oil in patients with intractable seizures. CBD oil, a derivative of the cannabis plant, is delivered orally as an oily liquid.

The oil used in the studies is produced under stringent requirements of the United States Food and Drug Administration by a licensed pharmaceutical company. It contains only traces of THC, the psychoactive component of marijuana. The process developed by GW Pharmaceuticals guarantees the consistency of the product that is provided to study participants.

About UAB

Known for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham is the state of Alabama’s largest employer and an internationally renowned research university and academic medical center; its professional schools and specialty patient-care programs are consistently ranked among the nation’s top 50. UAB’s Center for Clinical and Translational Science is advancing innovative discoveries for better health as a two-time recipient of the prestigious Center for Translational Science Award. Find more information at www.uab.edu and www.uabmedicine.org.

In a recent study, a simple exercise program carried out at home improved dialysis patients’ walking performance and quality of life. The findings appear in an upcoming issue of theJournal of the American Society of Nephrology(JASN).

Studies have suggested that physical exercise can provide benefits for dialysis patients. To see if something as simple as walking may have positive effects, a team led by Carmine Zoccali, MD (CNR-IFC, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, Italy), along with Fabio Manfredini, MD (University of Ferrara), and Francesca Mallamaci, MD (Reggio Cal Renal and Transplantation Unit and CNR), randomized 296 dialysis patients to normal physical activity or a low intensity exercise program—20 minutes of walking at low-moderate speed every second day—of gradually increasing intensity over 6 months (https://www.youtube.com/watch?v=ki8YX_t-0jA).

After 6 months, the distance covered during a 6-minute walking test improved in the exercise group (average distance: baseline 328 m; 6 months 367 m) but not in the control group (baseline 321 m; 6 months 324 m). Similarly, the 5 times sit-to-stand test time improved in the exercise group average time: baseline 20.5 seconds; 6 months 18.2 seconds) but not in the control group (baseline 20.9 seconds; 6 months 20.2 seconds). Cognitive function and quality of scores improved significantly in the exercise arm compared with the control arm.

“Poor physical functioning is perhaps the most pervasive and disabling disturbance in patients with advanced kidney disease who are on chronic dialysis,” said Dr. Zoccali. “While the effect of regular physical exercise training on physical performance in selected dialysis patients studied in standardized experimental settings in the laboratory is well documented, how exercise training should be articulated and implemented still remains an open problem. Our study shows that simple, home-based exercise programs hold potential for improving physical functioning in dialysis patients.”